Pyrrolothiazine and pyrrolothiazepine compounds having serotonin-2 receptor antagonistic and alpha-1-blocking action

ABSTRACT

A pyrrolesulfonamide derivative having the following formula (I):  
                 
 
     wherein the ring P represented by  
                 
 
     is a pyrrole ring having the following structure:  
                 
 
     wherein R represents alkyl, cycloalkyl, cycloalkyl-alkyl or aralkyl; the dashed line indicates the presence or absence of a bond; and, when the bond is present, Z 2  is not present and Z 1  represents H but, when the bond is absent, Z 1  represents H and Z 2  represents OH or Z 1  and Z 2  are combined together to represent O or a group NOR 1 , in which R 1  represents H, or alkyl, aralkyl or aryl; l stands for 0 or 1; A represents alkylene, alkenylene or alkynylene; and Y represents a group  
                 
 
     in which W represents CH, C═ or N; m stands for 0 or 1 when W is CH or N, or m stands for 1 when W is C═; B represents a specific divalent group; E 1  and E 2  each independently represents H or lower alkyl; and D represents an aromatic hydrocarbon group or heterocyclic group. The compound (I) has strong serotonin-2 receptor antagonistic action and low toxicity and less side effects, and is useful as a therapeutic for circulatory diseases such as ischemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances.

TECHNICAL FIELD

[0001] This invention relates to novel pyrrolesulfonamide derivatives.More specifically, this invention is concerned withpyrrolo[2,3-e][1,2]thiazine derivatives, pyrrolo[3,4-e][1,2]thiazinederivatives, pyrrolo[2,3-f][1,2]thiazepine derivatives andpyrrolo-[3,4-f][1,2]thiazepine derivatives, and salts thereof, saidderivatives and salts having strong serotonin-2 receptor antagonisticaction of excellent selectivity and being useful, for example, for theprevention or treatment of ischemic heart diseases such as anginapectoris, arrhythmia, myocardial infarction, congestive heart failureand post-PTCA restenosis, cerebrovascular disturbances such as cerebralinfarction and cerebral sequelae after subarachnoid hemorrhage,peripheral circulatory disturbances such as arteriosclerosis obliterans,thromboangiitis obliterans and Raynaud disease, and hypertension; theirpreparation processes; and pharmaceuticals containing them as effectiveingredients.

BACKGROUND ART

[0002] Serotonin is a compound contained abundantly in platelets, whichare a blood component, and in a central nervous system, it acts as aneurotransmitter. In platelets, it is released upon stimulation bythromboxane A₂, ADP, collagen or the like, and synergistically acts onrelease of various platelet aggregation factors through activation ofserotonin-2 receptors in the platelets and vascular smooth muscle cellsand also on vasoconstriction by norepinephrine through α₁ receptors,thereby inducing strong platelet aggregation and vasoconstriction [P. M.Vanhoutte, “Journal of Cardiovascular Pharmacology”, Vol. 17 (Supple.5), S6-S12 (1991)].

[0003] Serotonin is also known to potentiate proliferation of vascularsmooth muscle cells [S. Araki et al., “Atherosclerosis”, Vol. 83,pp.29-34 (1990). It has been considered that, particularly whenendothelial cells are injured as in arteriosclerosis or myocardialinfarction, the vasoconstricting action and thrombus forming action ofserotonin are exasperated, thereby reducing or even stopping bloodsupply to myocardial, cerebral and peripheral organs [P. Golino et al.,“The New England Journal of Medicine”, Vol. 324, No. 10,pp.641-648(1991), Y. Takiguchi et al., “Thrombosis and Haemostasis”,Vol. 68(4), pp.460-463(1992), A. S. Weyrich et al., “American Journal ofPhysiology”, Vol. 263, H349-H358(1992)]. Being attracted by such actionsof serotonin or serotonin-2 receptors, various attempts are now underway to use a serotonin-2 receptor antagonist as a pharmaceutical forischemic diseases of the heart, the brain and peripheral tissues.

[0004] Several compounds, led by sarpogrelate, are known to haveserotonin-2 receptor antagonistic action. They however do not includeanything having the pyrrolo[2,3-e][1,2]thiazine skeleton,pyrrolo[3,4-e][1,2]thiazine skeleton, pyrrolo[2,3-f][1,2]thiazepineskeleton or pyrrolo[3,4-f][1,2]thiazepine skeleton. Those known to haveserotonin-2 receptor antagonistic action are accompanied with manyproblems to be improved in potency, toxicity, side effects or the like.On the other hand, medicines which have anti-serotonin action andα₁-blocking action in combination are considered to become extremelyeffective medicines for the treatment and prevention of hypertension andischemic heart diseases, because they have possibility to reduce sideeffects, such as orthostatic hypotension and reflex tachycardia, inducedby antihypertensive action on the basis of the α₁-blocking action andhypertension is a serious risk factor for ischemic heart diseases.

DISCLOSURE OF THE INVENTION

[0005] In view of the foregoing circumstances, the present inventorshave proceeded with extensive research toward compounds which havestrong serotonin-2 receptor antagonistic action and low toxicity andless side effects and are useful for the treatment and prevention ofischemic heart diseases, cerebrovascular disturbances and peripheralcirculatory disturbances. As a result, it has been found thatpyrrolesulfonamides represented by the below-described formula (I) meetthe above conditions. It has also been found that the compoundsaccording to the present invention include those also having α₁-blockingaction in combination and that such compounds are useful asantihypertensives or the like having less side effects and are widelyusable for the treatment and prevention of circulatory diseases.

[0006] The present invention has been completed based on the abovedescribed findings. A first object of the present invention is toprovide a pyrrolesulfonamide derivative or a salt thereof, saidpyrrolesulfonamide derivative being represented by the following formula(I):

[0007] wherein

[0008] the ring P represented by

[0009] means a pyrrole ring represented by the following structure:

[0010] in which R represents an alkyl group, a cycloalkyl group, acycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

[0011] the dashed line indicates the presence or absence of a bond; and,when the bond indicated by the dashed line is present, Z₂ is not presentand Z₁ represents a hydrogen atom but, when the bond indicated by thedashed line is absent, Z₁ represents a hydrogen atom and Z₂ represents ahydroxyl group; or Z₁ and Z₂ are combined together to represent anoxygen atom or a group NOR₁ in which R₁ represents a hydrogen atom, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaralkyl group or a substituted or unsubstituted aryl group;

[0012] l represents 0 or 1;

[0013] A represents a substituted or unsubstituted alkylene group, asubstituted or unsubstituted alkenylene group or a substituted orunsubstituted alkynylene group; and

[0014] Y represents a group

[0015] in which W represents CH, C═ or a nitrogen atom; and, when Wrepresents CH, m stands for 0 or 1, B represents a carbonyl group, asulfonyl group, an alkylene group, an alkenylene group, a group—C(OH)R₂— in which R₂ represents a substituted or unsubstituted arylgroup, a group —CHR₃— in which R₃ represents a substituted orunsubstituted aryl group, or a substituted or unsubstituted cyclic oracyclic acetal group; when W represents C═, m stands for 1, B representsa group

[0016] in which the double bond is coupled with W and R₄ represents asubstituted or unsubstituted aryl group or a substituted orunsubstituted aralkyl group; when W represents a nitrogen atom, m standsfor 0 or 1, and B represents a carbonyl group, a sulfonyl group, analkylene group, an alkenylene group or a group —CHR₅— in which R₅represents a substituted or unsubstituted aryl group; E₁ and E₂ eachindependently represents a hydrogen atom or a lower alkyl group; and Drepresents a substituted or unsubstituted aromatic hydrocarbon group ora substituted or unsubstituted aromatic heterocyclic group.

[0017] Another object of the present invention is to provide apreparation process of the pyrrolesulfonamide derivative (I) or itssalt.

[0018] A further object of the present invention is to provide apharmaceutical which comprises the pyrrole-sulfonamide derivative (I) orits pharmaceutically-acceptable salt as an effective ingredient and isusable for the treatment or the like of circulatory diseases.

BEST MODES FOR CARRYING OUT THE INVENTION

[0019] In the pyrrolesulfonamide derivatives (I) of the presentinvention, the ring P represents one of the following pyrrole rings:

[0020] wherein R has the same meaning as defined above.

[0021] Preferred examples of the group R bonded to the nitrogen atom ofthe pyrrole ring can include linear or branched alkyl groups having 1-8carbon atoms preferably, such as methyl, ethyl, n-propyl, isopropyl andn-pentyl; cycloalkyl groups having 3-8 carbon atoms, such ascyclopropyl, cyclopentyl and cyclohexyl; cycloalkyl-alkyl groups having4-8 carbon atoms, such as cyclopropylmethyl, cyclohexylmethyl andcyclohexylethyl; and aralkyl groups having 7-22 carbon atoms, such asdiphenylmethyl, benzyl and phenethyl. For example, one or more hydrogenatoms of each of these groups may be substituted by a like number ofhalogen atoms such as fluorine, chlorine and/or bromine atoms, alkylgroups having 1-4 carbon atoms preferably, such as methyl and/or ethyl,and/or alkoxy groups having 1-4 carbon atoms preferably, such as methoxyand/or ethoxy. Among these, particularly preferred are methyl and ethyl.

[0022] Further, l stands for 0 or 1 in the compound (I) according to thepresent invention. As the combination between the ring P and l,preferred examples can be (A) and 1, (A) and 0, and (B) and 1. Of these,the combinations of (A) and 1 and (A) and 0 are particularly preferred.

[0023] On the other hand, preferred examples of the group A in thecompound (I) according to the present invention can include linear orbranched alkylene groups having 2-10 carbon atoms, such as ethylene,trimethylene, tetramethylene, pentamethylene and octamethylene; linearor branched alkenylene groups having 4-10 carbon atoms, such as2-butenylene and 3-pentenylene; and linear or branched alkynylene groupshaving 4-10 carbon atoms, such as 2-butynylene and 3-pentynylene. One ormore of the hydrogen atoms of each of these groups may be substituted bya like number of halogen atoms such as fluorine, chlorine and/or bromineatoms. Among the above groups, trimethylene and tetramethylene areparticularly preferred.

[0024] Further, preferred examples of the group Z₁ and the group Z₂ inthe compound (I) according to the present invention can include thefollowing combinations: when the bond indicated by the dashed line ispresent, Z₂ is not present and Z₁ represents a hydrogen atom; when thebond indicated by the dashed line is absent, Z₁ represents a hydrogenatom and Z₂ represents a hydroxyl group, or Z₁ and Z₂ are combinedtogether to represent an oxygen atom or the group NOR₁.

[0025] Preferred examples of R₁ in the group NOR₁ can include a hydrogenatom; linear or branched alkyl groups having 1-4 carbon atomspreferably, such as methyl and ethyl; aryl groups having 6-14 carbonatoms, such as phenyl and naphthyl; and aralkyl groups having 7-22carbon atoms, such as benzyl and phenethyl. One or more of the hydrogenatoms of each of these groups may be substituted by a like number ofhalogen atoms such as fluorine, chlorine and/or bromine atoms, alkylgroups having 1-4 carbon atoms preferably, such as methyl and/or ethyl,and/or alkoxy groups having 1-4 carbon atoms preferably, such as methoxyand/or ethoxy. Of these, hydrogen atom and methyl group are particularlypreferred.

[0026] In the compound (I) according to the present invention, Y is agroup

[0027] wherein B, D, E₁, E₂, W and m have the same meanings as definedabove. The group represented by the following formula:

[0028] wherein E₁, E₂ and W have the same meanings as defined above is aheterocyclic group derived from piperidine or piperazine, and two orless of the hydrogen atoms on the ring may be substituted by a likenumber of alkyl groups having 1-4-carbon-atoms preferably, such asmethyl and/or ethyl.

[0029] When the above group is a heterocyclic group derived frompiperidine, m stands for 0 or 1 (with the proviso that m stands for 1when W represents C═), and B represents a carbonyl group, a sulfonylgroup, an alkylene group (an alkylene group having 1-4 carbon atomspreferably, with a methylene group being particularly preferred), analkenylene group (an alkenylene group having 2-5 carbon atomspreferably, with a 2-propenylene group being particularly preferred), agroup —C(OH)R₂— in which R₂ is an aryl group having 6-14 carbon atoms,such as phenyl or naphthyl, in which one or more of the hydrogen atomsmay be substituted, a group —CHR₃— in which R₃ is an aryl group having6-14 carbon atoms, such as phenyl or naphthyl, in which one or more ofthe hydrogen atoms may be substituted, a group

[0030] in which the double bond is coupled with W, R₄ represents an arylgroup having 6-14 carbon atoms, such as phenyl or naphthyl, or anaralkyl group having 7-22 carbon atoms, such as benzyl or phenethyl, andthese groups may be in substituted forms, or a cyclic or acyclic acetalgroup in which one or more of the hydrogen atoms may be substituted.

[0031] Exemplary cyclic or acyclic acetal groups include:

[0032] In the above-described definition of B, preferred examples ofsubstituents on the groups R₂, R₃ and R₄ can include one or more alkylgroups having 1-4 carbon atoms, such as methyl and ethyl; aryl groupshaving 6-14 carbon atoms, such as phenyl and naphthyl; halogen atomssuch as fluorine atoms, chlorine atoms and bromine atoms; alkoxy groupshaving 1-4 carbon atoms, such as methoxy and ethoxy; hydroxyl groups;cyano groups; and nitro groups.

[0033] Further, illustrative of substituents on the cyclic or acyclicacetal are halogen atoms such as fluorine atoms, chlorine atoms, andbromine atoms; alkyl groups having 1-4 carbon atoms, such as methyl andethyl; aryl groups having 6-14 carbon atoms, such as phenyl andnaphthyl; aralkyl groups having 7-22 carbon atoms, such as benzyl andphenethyl; and alkylidene groups having 1-4 carbon atoms preferably,such as methylidene and ethylidene.

[0034] As a particularly preferred example of B, a carbonyl group can bementioned.

[0035] When the heterocyclic group is a group derived from piperazine, mstands for 0 or 1 (preferably 0), and B represents a carbonyl group, asulfonyl group, an alkylene group (preferably, an alkylene group having1-4 carbon atoms, with a methylene group being particularly preferred),an alkenylene group (preferably, an alkenylene group having 3-6 carbonatoms, with a 2-propenylene group being particularly preferred), a group—CHR₅— in which R₅ represents an aryl group having 6-14 carbon atoms,such as phenyl or naphthyl.

[0036] The above-described R₅ may be substituted further, for example,by one or more of halogen atoms such as fluorine, chlorine and/orbromine, alkyl groups having 1-4 carbon atoms preferably, such as methyland/or ethyl, alkoxy groups having 1-4 carbon atoms preferably, such asmethoxy and/or ethoxy, hydroxyl groups, and/or the like.

[0037] As a preferred example of the above-described B, a substituted orunsubstituted phenylmethylene group can be mentioned.

[0038] Preferred examples of group D can include aromatic hydrocarbongroups having 6-28 carbon atoms preferably, such as a phenyl group inwhich one or more of the hydrogen atoms may be substituted and anaphthyl group in which one or more of the hydrogen atoms may besubstituted.

[0039] Other preferred examples of D can include aromatic heterocyclicgroups, preferably those each of which is monocyclic or bicyclic andcontains three or less hetero atoms, such as pyridyl, pyrimidinyl,benzisothiazolyl, benzisoxazolyl, indazolyl and indolyl groups in whichone or more of hydrogen atoms may be substituted. Examples of the heteroatoms can include oxygen, sulfur and nitrogen atoms.

[0040] Examples of the substituents for the above aromatic hydrocarbongroup or aromatic heterocyclic group can include halogen atoms such asfluorine, chlorine and bromine; alkyl groups having 1-4 carbon atomspreferably, such as methyl and ethyl; alkoxyl groups having 1-4 carbonatoms preferably, such as methoxy and ethoxy; aryl groups having 6-14carbon atoms, such as phenyl and naphthyl; aralkyl groups having 7-22carbon atoms, such as benzyl and phenethyl; aralkyloxy groups having7-22 carbon atoms preferably, such as benzyloxy; cyano groups; nitrogroups; carboxyl groups; alkoxycarbonyl groups (with an alcohol moietythereof having 1-6 carbon atoms preferably); lower alkylsulfonylaminogroups (with an alkyl moiety thereof having 1-4 carbon atomspreferably); carbamoyl groups; and hydroxyl groups.

[0041] Among these examples of group D, preferred ones can includephenyl groups which may be unsubstituted or substituted by one or moreof halogen atoms, alkoxy groups and/or hydroxyl groups; benzisothiazolylgroups which may be unsubstituted or substituted by one or more halogenatoms; benzisoxazolyl groups which may be unsubstituted or substitutedby one or more halogen atoms; and indazolyl groups which may beunsubstituted or substituted by one or more halogen atoms. Particularlypreferred are an unsubstituted phenyl group; and phenyl groupssubstituted by one or more of fluorine atoms, methoxy groups and/orhydroxyl groups.

[0042] Many of the compounds (I) according to the present invention haveisomers. It is to be noted that these isomers and mixtures thereof areall embraced by the present invention.

[0043] The pyrrolesulfonamide derivatives (I) according to the presentinvention can be prepared by various processes. It is however preferredto prepare each of them, for example, by using a pyrrolesulfonamidederivative (IIa) or (IIa′), which is available by Process 1 to bedescribed below, and following any one of the processes to be describedas Process 2 onwards.

[0044] Process 1:

[0045] Pyrrolesulfonamide derivatives (IIa) and (IIa′) useful asstarting materials can be synthesized, for example, by the followingprocess:

[0046] Process (a)

[0047] Compounds represented by the formula (IIa) and (IIa′) can beobtained in accordance with the following reaction scheme, namely, byconverting a 1-substituted pyrrole-3-sulfonic acid represented by theformula (XII) or a salt thereof into a 1-substituted pyrrole-3-sulfonylhalide represented by the formula (XIII), reacting glycine, β-alanine ora derivative thereof represented by the formula (XIV) or an organic orinorganic acid salt thereof with the compound (XIII) and, if necessary,conducting deprotection to obtain a compound represented by the formula(XV) and then subjecting the thus-obtained compound to a ring-closingreaction.

[0048] wherein M represents a hydrogen ion, an alkali metal ion, analkaline earth metal ion or a quaternary ammonium ion, p stands for 1when M represents a hydrogen ion, an alkali metal ion or a quaternaryammonium ion or p stands for 2 when M represents an alkaline earth metalion, q stands for 0 or 1, R₆ represents a hydrogen atom or acarboxyl-protecting group, X″ represents a chlorine atom or a bromineatom, and R and l have the same meanings as defined above.

[0049] Illustrative of M in the compound represented by the formula(XII) in the above scheme are hydrogen ion; alkali metal ions such assodium ion and potassium ion; alkaline earth metal ions such as bariumion; and quaternary ammonium ions such as pyridinium ion. Asrepresentative preparation processes of the compound represented by theformula (XII), the following two processes can be mentioned.

[0050] [Preparation Process of the Compound (XII)-1]

[0051] The compound represented by the formula (XII) can be obtained inaccordance with the following formula, namely, by causing a sulfonatingagent such as sulfur trioxide-pyridine complex to act on a 1-substitutedpyrrole (XVIII) and, if necessary, treating the resultant compound withan acid such as hydrochloric acid or sulfuric acid or a base such assodium hydroxide, sodium carbonate, sodium hydrogencarbonate or bariumhydroxide.

[0052] wherein M, R, p and q have the same meanings as defined above.

[0053] [Preparation Process of the Compound (XII)-2]

[0054] The compound represented by the formula (XII) can be obtained inaccordance with the following formula, namely, by causing trimethylsilylchlorosulfonate (XIX) to act on a1-substituted-2-tri-n-butylstannylpyrrole represented by the formula(XVII) in a solvent, which does not take part in the reaction, such ascarbon tetrachloride or 1,2-dichloroethane and then hydrolyzing theresultant compound. Here, a basic substance may be allowed to existconcurrently, whereby the reaction product can be obtained as a salt.

[0055] wherein M, R, p and q have the same meanings as defined above.

[0056] Further, the compound (XIII) can be obtained by causingphosphorus pentachloride or phosphorus pentabromide to act on thecompound (XII) in a solvent which does not take part in the reaction,such as ethyl ether or toluene.

[0057] In addition, as the carboxyl-protecting group represented by thegroup R₆ in the compound (XIV), it is possible to use, in addition tolower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl and t-butyl and aralkyl groups having 7-20 carbon atoms, suchas benzyl and 9-anthrylmethyl, conventional protecting groups such asthose described in T. W. Greene: “Protective Groups in organicSynthesis” (John Wiley & Sons, Inc.) and the like.

[0058] Further, as an illustrative synthesis process of the compound(XV), a process can be mentioned in which a base is added to thecompound (XIII), as needed, and glycine, β-alanine or a derivativethereof or an organic or inorganic acid salt thereof is caused to act.Usable examples of the base can include organic bases such astriethylamine and pyridine, and inorganic bases such as sodiumhydrogencarbonate, potassium carbonate and sodium hydroxide.

[0059] The compound (XV) so obtained is subjected to a cyclizingreaction, optionally after removing the protecting group by virtue of asuitable method such as the action of an acid or a base, or catalyticreduction. This cyclizing reaction is conducted by treating the compound(XV) together with an organic acid such as methanesulfonic acid, aninorganic acid such as sulfuric acid or polyphosphoric acid or a mixtureof such an organic or inorganic acid and phosphorus pentoxide at roomtemperature to 170° C., preferably at 80-120° C.

[0060] In this case, a solvent which does not take part in the reactionmay be added as needed.

[0061] Further, the cyclizing reaction can also be practiced by,optionally after addition of a catalyst such as dimethylformamide to thecompound (XV) in which R₆ is a hydrogen atom, treating the compound withoxalyl chloride, thionyl chloride, thionyl bromide, oxalyl bromide,phosgene, phosphorus trichloride, phosphorus tribromide, phosphorylchloride, phosphoryl bromide or the like to convert it into itscorresponding acid halide and then treating the acid halide at −20° C.to reflux temperature in the presence of a Lewis acid such as aluminumchloride, aluminum bromide, boron trifluoride-ether complex or tintetrachloride in a solvent such as dichloromethane, 1,2-dichloroethaneor nitromethane. In the above-described reactions, the compound (IIa)and the compound (IIa′) can be formed at varied ratios by changing thereaction conditions.

[0062] Process (b)

[0063] Compounds represented by the formula (IIb) and (IIb′) can beobtained in accordance with the following reaction scheme, namely, byconverting a pyrrole-3-sulfonic acid represented by the formula (XX) ora salt thereof into a pyrrole-3-sulfonyl halide represented by theformula (XXI), reacting glycine, β-alanine or a derivative thereofrepresented by the formula (XIV) or an organic or inorganic acid saltthereof with the compound (XXI) and, if necessary, conductingdeprotection to obtain a compound represented by the formula (XXII) andthen subjecting the thus-obtained compound to a ring-closing reaction.The compound (Ila) and compound (IIa′) can then be obtained byintroducing groups R to the pyrrole-nitrogen atoms of the compounds(IIb), (IIb′), respectively.

[0064] wherein X″′ represents an eliminative group, and M, R, R₆, X″, land p have the same meanings as defined above.

[0065] In the above scheme, the compound represented by the formula (XX)can be synthesized from pyrrole as a starting material by following thepreparation process of the compound (XII)-1 under Process (a) ofProcess 1. Further, the conversion of the compound (XX) into thecompound (IIb) and the compound (IIb′) can be effected in a similarmanner as in the conversion of the compound (XII) into the compound(IIa) and the compound (IIa′) in Process (a) of Process 1.

[0066] The conversion from the compound (IIb) into the compound (IIa)can be effected by treating the compound (IIb) with an organic orinorganic base and then reacting the compound represented by the formula(XVIa) or (XVIb), or by causing the compound (XVIa) or the compound(XVIb) to act on the compound (IIb) in the presence of such a base.

[0067] Examples of the eliminative group represented by the group X″′ inthe compound (XVIa) can include halogen atoms such as chlorine, bromineand iodine, alkylsulfonyloxy groups such as methanesulfonyloxy, andarylsulfonyloxy groups such as p-toluenesulfonyloxy. Exemplary organicor inorganic bases can include potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, sodium hydride, triethylamine,sodium methoxide, and potassium t-butoxide. Further, illustrativesolvents usable in the above reaction include acetone, 2-butanone,acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, anddimethylsulfoxide. The reaction is conducted at −20° C. to refluxtemperature.

[0068] On the other hand, the conversion from the compound (IIb′) intothe compound (IIa′) can also be effected under the same conditions as inthe above-described conversion from the compound (IIb) into the compound(IIa).

[0069] Process 2:

[0070] Among the pyrrolesulfonamide derivatives (I), compounds (Ia) ineach of which Z₁ and Z₂ are combined together to represent an oxygenatom can be synthesized, for example, by any one of the followingprocesses.

[0071] Process (a)

[0072] Each compound (Ia) can be obtained in accordance with thefollowing reaction scheme, namely, by reacting a compound represented bythe formula (II) with a compound represented by the formula (III) toconvert the compound (II) into a compound represented by the formula(IV) and then reacting a nitrogen-containing compound represented by theformula (V) or a salt thereof with the compound (IV).

[0073] wherein X and X′ represent the same or different eliminativegroups, and A, the ring P, Y and l have the same meanings as definedabove.

[0074] In the above-described reaction, the conversion from the compound(II) into the compound (IV) can be effected by treating the compound(II) with an organic or inorganic base and then reacting the compound(III) with the compound (II), or by causing the compound (III) to act onthe compound (II) in the presence of such a base.

[0075] The groups X and X′ in the compound (III) are eliminative groups.Illustrative can be halogen atoms such as chlorine and bromine,alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxygroups such as p-toluenesulfonyloxy.

[0076] Exemplary inorganic bases or organic bases can include sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,sodium hydride, triethylamine, sodium ethoxide, sodiumbis(trimethylsilyl)amide, and potassium t-butoxide. The reaction can beconducted at −78° C. to reflux temperature in a solvent which does nottake part in the reaction.

[0077] To prepare the compound (Ia) from the thus-obtained compound (IV)and the nitrogen-containing compound (V), it is only necessary to reactthe nitrogen-containing compound (V) or an organic acid salt orinorganic acid salt thereof with the compound (IV), optionally togetherwith an organic base such as triethylamine, pyridine, collidine orpotassium t-butoxide or an inorganic base such as potassium carbonate,sodium carbonate, sodium hydrogencarbonate, sodium hydroxide or sodiumhydride and optionally with the addition of an alkali iodide such aspotassium iodide or sodium iodide, in a solventless manner or in asolvent such as acetone, 2-butanone, acetonitrile, dimethylformamide,methanol, ethanol or the like at room temperature to 150° C.

[0078] Examples of the nitrogen-containing compound (V) can include1-phenylpiperazine, 1-(2-fluorophenyl)-piperazine,1-(3-fluorophenyl)piperazine, 1-(4-fluorophenyl)piperazine,1-(4-hydroxyphenyl)piperazine, 1-(2-chlorophenyl)piperazine,1-(3-chlorophenyl)piperazine, 1-(4-chlorophenyl)piperazine,1-(2-methoxyphenyl)piperazine, 1-(3-methoxyphenyl)piperazine,1-(4-methoxyphenyl)piperazine, 1-(4-methanesulfonamidophenyl)piperazine,1-(4-cyanophenyl)piperazine, 1-(4-carbamoylphenyl)piperazine,1-(4-methoxycarbonylphenyl)piperazine, 1-(2-pyridyl)piperazine,1-(2-pyrimidinyl)piperazine, 1-benzylpiperazine,1-diphenylmethylpiperazine, 1-cinnamylpiperazine, 1-benzoylpiperazine,1-(4-benzyloxybenzoyl)piperazine, 1-(4-hydroxybenzoyl)piperazine,1-(2-furoyl)piperazine, 1-(1,2-benzisoxazol-3-yl)piperazine,4-phenylpiperidine, 4-benzylpiperidine,α,α-bis(4-fluorophenyl)-4-piperidinemethanol,4-(4-fluorobenzoyl)piperidine, 4-benzoylpiperidine,4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine,4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine,4-(6-fluoro-1H-indazol-3-yl)piperidine,4-[(4-fluorophenyl)sulfonyl]piperidine,4-[bis(4-fluorophenyl)methylene]piperidine, and4-(4-fluorobenzoyl)piperidine ethylene acetal.

[0079] These compounds are either known in the art or readily availableby processes known per se in the art or by processes similar to suchknown processes.

[0080] Process (b)

[0081] Further, the compound (Ia) can also be obtained by causing anitrogen-containing compound represented by the formula (VI) to act onthe compound represented by the formula (II) in accordance with thefollowing reaction formula:

[0082] wherein A, the ring P, X, Y and l have the same meanings asdefined above.

[0083] The conversion from the compound (II) into the compound (Ia) isconducted by causing the compound (VI) to act either after treatment ofthe compound (II) with an inorganic base or an organic base or in thepresence of an inorganic base or an organic base. Reaction conditionsare similar to those employed upon conversion from the compound (II)into the compound (IV) and described above under Process (a) of Process2. Further, the compound (VI) can be synthesized by reacting thecompound (III) with the compound (V) in a manner known per se in theart.

[0084] Process 3:

[0085] Among the pyrrolesulfonamide derivatives (I), the compounds (Ic)and (Ie) in each of which Z₁ and Z₂ are combined together to represent agroup NOR₁ can each be synthesized by any one of the followingprocesses.

[0086] Process (a)

[0087] Each compound (Ie) is obtained in accordance with the followingreaction scheme, namely, by causing hydroxylamine or a derivativethereof (VII) or a salt thereof to act on a compound represented by theformula (IV) and then causing a nitrogen-containing compound (V) to act.

[0088] wherein A, the ring P, R₁, X, Y and l have the same meanings asdefined above.

[0089] The reaction between the compound (IV) and the hydroxylamine orits derivative (VII) is effected, if necessary, in the presence of anorganic base such as pyridine, triethylamine, collidine or sodiumacetate or an inorganic base such as potassium carbonate or sodiumhydroxide. The hydroxylamine or its derivative (VII) may also be used inthe form of an organic acid salt or an inorganic acid salt.

[0090] The reaction is conducted at 0° C. to reflux temperature,preferably 0° C.-100° C. by using a suitable solvent, for example,methanol, ethanol, propanol, tetrahydrofuran, dimethylformamide ordimethylsulfoxide as needed.

[0091] Further, the conversion from the thus-obtained compound (VIII)into the compound (Ie) can be effected under similar conditions as inthe conversion from the compound (IV) into the compound (Ia) shown aboveunder Process (a) of Process 2.

[0092] Process (b)

[0093] Each compound (Ic) is obtained by causing hydroxylamine or itsderivative (VII) or a salt thereof to act on a compound (Ib) inaccordance with the following reaction formula.

[0094] wherein A, the ring P, R₁ and l have the same meanings as definedabove, and Y′ represents a group

[0095] in which when W represents CH, B′ represents a sulfonyl group, analkylene group, an alkenylene group, a group —C(OH)R₂— in which R₂represents a substituted or unsubstituted aryl group, a group —CHR₃— inwhich R₃ represents a substituted or unsubstituted aryl group, or asubstituted or unsubstituted cyclic or acyclic acetal group; when Wrepresents C═, B′ represents a group

[0096] in which the double bond is coupled with W and R₄ represents asubstituted or unsubstituted aryl group or a substituted orunsubstituted aralkyl group; when W represents a nitrogen atom, B′represents a carbonyl group, a sulfonyl group, an alkylene group, analkenylene group or a group —CHR₅— in which R₅ represents a substitutedor unsubstituted aryl group; and D, E₁, E₂ and m have the same meaningsas defined above.

[0097] The conversion from the compound (Ib) into the compound (Ic) canbe effected under similar conditions as the conversion from the compound(IV) into the compound (VIII) shown above under Process (a) of Process3.

[0098] Process 4:

[0099] Among the pyrrolesulfonamide derivatives (I), the compounds (Id)and (If) in each of which Z₁ represents a hydrogen atom and Z₂represents a hydroxyl group can each be synthesized by any one of thefollowing processes.

[0100] Process (a)

[0101] Each compound (If) is obtained in accordance with the followingreaction scheme, namely, by reducing a compound represented by theformula (IV) and then causing a nitrogen-containing compound (V) to act.

[0102] wherein A, the ring P, X, Y and l have the same meanings asdefined above.

[0103] The conversion from the compound (IV) into the compound (IX) isconducted by treating the compound represented by the formula (IV) witha reducing agent such as sodium borohydride, potassium borohydride orsodium cyanoborohydride at −78° C. to reflux temperature, preferably−20° C. to room temperature in a conventionally used solvent.

[0104] The conversion from the compound (IX) into the compound (If) canbe effected under similar conditions as the conversion from the compound(IV) into'the compound (Ia) shown above under Process (a) of Process 2.

[0105] Process (b)

[0106] Each compound (Id) is obtained by reducing a compound representedby the formula (Ib) in accordance with the following reaction formula.

[0107] wherein A, the ring P, Y′ and l have the same meanings as definedabove.

[0108] The conversion from the compound (Ib) into the compound (Id) canbe effected under similar conditions as in the conversion from thecompound (IV) into the compound (IX) shown above under Process (a) ofProcess 4.

[0109] Process 5:

[0110] Among the pyrrolesulfonamide derivatives (I), the compounds (Ig)in each of which the bond indicated by the dashed line is present and Z₁represents a hydrogen atom can be synthesized by any one of thefollowing processes.

[0111] Process (a)

[0112] Each compound (Ig) is obtained in accordance with the followingreaction scheme, namely, by subjecting a compound represented by theformula (IX) to a dehydration reaction to obtain a compound representedby the formula (X) and then causing a nitrogen-containing compound (V)to act on the compound (X).

[0113] wherein A, the ring P, X, Y and l have the same meanings asdefined above.

[0114] In the above-described reaction, the conversion from the compound(IX) into the compound (X) can be effected by treating the compound (IX)with an acid such as hydrogen chloride, hydrogen bromide, sulfuric acid,methanesulfonic acid or p-toluenesulfonic acid at −20° C. to 100° C.,preferably at −20° C. to room temperature in a solvent such as water,methanol, ethanol, ethyl acetate, chloroform or toluene.

[0115] As an alternative, the conversion into the compound (X) can alsobe effected by causing methanesulfonyl chloride, p-toluenesulfonylchloride, phosphorus trichloride, phosphorus oxychloride, thionylchloride or the like and a base such as triethylamine, pyridine orcollidine to act on the compound (IX), if necessary, in a solvent suchas dichloromethane, chloroform or toluene.

[0116] The conversion from the compound (X) into the compound (Ig) canbe effected under similar conditions as in the conversion from thecompound (IV) into the compound (Ia) described above under Process (a)of Process 2.

[0117] Process (b)

[0118] Each compound (Ig) is obtained by subjecting a compoundrepresented by the formula (If) to a dehydration reaction in accordancewith the following reaction formula:

[0119] wherein A, the ring P, Y and l have the same meanings as definedabove.

[0120] In the above-described reaction, the conversion from the compound(If) into the compound (Ig) can be effected under similar conditions asin the conversion from the compound (IX) into the compound (X) describedabove under Process (a) of Process 5.

[0121] If necessary, the compounds (I) of the present invention obtainedaccording to the above-described processes can each be reacted with oneof various acids to convert the compound into its salt. Then, theresulting salt can be purified by a method such as recrystallization orcolumn chromatography.

[0122] Exemplary acids usable for the conversion of thepyrrolesulfonamide derivatives (I) into their salts can includeinorganic acids such as hydrochloric acid, nitric acid, sulfuric acid,phosphoric acid and hydrobromic acid; and organic acids such as maleicacid, fumaric acid, tartaric acid, lactic acid, citric acid, aceticacid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid,palmitic acid and tannic acid.

[0123] Further, the compounds (I) according to the present inventioninclude those containing asymmetric centers. Each racemic mixture can beisolated by one or more of various methods, whereby a singleoptically-active substance can be obtained. Usable methods include, forexample:

[0124] (1) Isolation by an optically active column.

[0125] (2) Isolation by recrystallization subsequent to conversion intoa salt with an optically active acid.

[0126] (3) Isolation by an enzyme reaction.

[0127] (4) Isolation by a combination of the above methods (1) to (3).

[0128] The pyrrolesulfonamide derivatives (I) and their salts, which areobtained as described above, have strong serotonin-2 blocking action aswill be demonstrated in tests to be described subsequently herein.Moreover, the compounds (I) according to the present invention have alsobeen found to include those also having α₁ blocking action. From theresults of toxicity tests, the compounds (I) according to the presentinvention have also been found to possess high safety.

[0129] The compounds (I) according to the present invention cantherefore be used as pharmaceuticals for the treatment of circulatorydiseases such as ischemic heart diseases, cerebrovascular disturbances,peripheral circulatory disturbances and hypertension.

[0130] When the pyrrolesulfonamide derivatives (I) According to thisinvention are used as pharmaceuticals, they can be administered in aneffective dose as they are. As an alternative, they can also beformulated into various preparation forms by known methods and thenadministered.

[0131] Exemplary preparation forms as medicines include orallyadministrable preparation forms such as tablets, powders, granules,capsules and syrups as well as parenterally administrable preparationforms such as injections and suppositories. Whichever preparation formis used, a known liquid or solid extender or carrier usable for theformulation of the preparation form can be employed.

[0132] Examples of such extender or carrier includepolyvinylpyrrolidone, arabic gum, gelatin, sorbit, cyclodextrin,tragacanth gum, magnesium stearate, talc, polyethylene glycol, polyvinylalcohol, silica, lactose, crystalline cellulose, sugar, starch, calciumphosphate, vegetable oil, carboxymethylcellulose, sodium laurylsulfate,water, ethanol, glycerin, mannitol, syrup, and the like.

[0133] When the compounds (I) according to the present invention areused as pharmaceuticals, their dose varies depending on theadministration purpose, the age, body weight, conditions, etc. of thepatient to be administered. In oral administration, the daily dose maygenerally be about 0.01-1,000 mg.

[0134] The present invention will next be described in further detail bythe following referential examples, examples and tests. It is however tobe noted that the present invention is by no means limited to thefollowing examples.

REFERENTIAL EXAMPLE 1

[0135] Synthesis of sodium 3-pyrrolesulfonate (Compound 1)

[0136] A mixture consisting of 30.0 g (447 mmol) of pyrrole, 75.0 g (471mmol) of sulfur trioxide-pyridine complex and 250 ml of1,2-dichloroethane was refluxed for 16 hours. The top layer of thereaction mixture was removed by decantation. To the residue, 150 ml ofwater and 30 g of sodium carbonate were added successively. After theresulting mixture was boiled, the solvent was distilled off underreduced pressure. Ethanol-water (9:1 v/v, 500 ml) was added to theresidue, followed by reflux for 1 hour. The reaction mixture wassubjected to hot filtration, and the filtrate was allowed to cool down.Precipitated crystals were collected, washed with chilled ethanol anddiethyl ether, and then dried under reduced pressure, whereby 17.0 g ofpowdery crystals were obtained.

REFERENTIAL EXAMPLE 2

[0137] Synthesis of Benzyl 2-(3-pyrrolesulfonamide)acetate (Compound 2)

[0138] A suspension of 16.9 g (100 mmol) of Compound 1 and 22.9 g (110mmol) of phosphorus pentachloride in 750 ml of diethyl ether was stirredat room temperature for 2 hours, and was then refluxed for 4 hours.After the reaction mixture was allowed to cooled down, it was filtered.The filtrate was washed successively with ice water (twice), a chilled,saturated aqueous solution of sodium hydrogencarbonate, ice water and achilled, saturated aqueous solution of sodium chloride. The organiclayer was dried over anhydrous sodium sulfate and then concentratedunder reduced pressure, whereby 11.2 g of 3-pyrrolesulfonyl chloridewere obtained as crude crystals.

[0139] After a mixture consisting of the whole amount of thethus-obtained crude crystals, 32.6 g (96.6 mmol) of glycine benzyl esterp-toluenesulfonate, 19.6 g (193 mmol) of triethylamine and 250 ml oftetrahydrofuran (hereinafter called “THF”) was refluxed for 6 hours, thereaction mixture was concentrated under reduced pressure. Ethyl acetatewas added to the residue. The resulting mixture was washed successivelywith a 10% aqueous solution of citric acid, water and a saturatedaqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The residue wastreated with activated carbon under heat in methanol and thenrecrystallized from methanol, whereby 12.6 g of the title compound wereobtained (yield: 43% based on sodium 3-pyrrolesulfonate).

REFERENTIAL EXAMPLE 3

[0140] Synthesis of Benzyl 3-(3-pyrrolesulfonamide)propionate (Compound3)

[0141] A mixture consisting of 1.66 g (10 mmol) of 3-pyrrolesulfonylchloride obtained by the process of Referential Example 2, 7.03 g (20mmol) of β-alanine benzyl ester p-toluenesulfonate, 4.05 g (40 mmol) oftriethylamine and 100 ml of THF was refluxed for 16 hours. The reactionmixture was concentrated under reduced pressure, and ethyl acetate wasadded to the residue. The organic layer was washed successively with asaturated aqueous solution of sodium hydrogencarbonate, water, a 10%aqueous solution of citric acid, water and a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (Merck & Co. Inc. No. 9385) (the samesilica gel were used in the subsequent examples) (eluent: ethylacetate/hexane=1/1), whereby 2.82 g of the title compound wereobtained-(yield: 92%).

REFERENTIAL EXAMPLE 4

[0142] Synthesis of 2-(3-pyrrolesulfonamide)acetic Acid (Compound 4)

[0143] To a solution of 4.85 g (16 mmol) of Compound 2 in 150 ml of THF,480 mg of 10% palladium on charcoal were added, followed by stirring atroom temperature for 15 hours under a hydrogen gas stream. The reactionmixture was filtered and the filtrate was concentrated under reducedpressure. The residue was recrystallized from acetonitrile, whereby 2.87g of the title compound were obtained (yield: 88%).

REFERENTIAL EXAMPLE 5

[0144] Synthesis of 3-(3-pyrrolesulfonamide)propionic Acid (Compound 5)

[0145] To a solution of 19.60 g (64 mmol) of Compound 3 in 400 ml ofTHF, 1.96 g of 5% palladium on charcoal were added, followed by stirringat room temperature for 4 hours under a hydrogen gas stream. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was recrystallized from ethyl acetate,whereby 11.96 g of the title compound were obtained (yield: 86%).

REFERENTIAL EXAMPLE 6

[0146] Synthesis of 2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazin-4-one1,1-dioxide (Compound 6) and2,3,4,6-tetrahydropyrrolo[3,4-e][1,2]thiazin-4-one 1,1-dioxide (Compound7)

[0147] Under ice cooling, 5.00 g (24.5 mmol) of Compound 4, 4.27 ml (49mmol) of oxalyl chloride, 120 ml of THF and 3 droplets of DMF weremixed, and the resulting mixture was stirred for 1 hour. The reactionmixture was concentrated under reduced pressure, and 120 ml of1,2-dichloroethane were added to the residue. Under ice-cooled stirring,6.53 g (49 mmol) of aluminum chloride were added, followed by stirringfor 2.5 hours at the same temperature. Under ice cooling, 43 ml of 6 Nhydrochloric acid were added. After the resultant mixture was saturatedwith sodium chloride, the thus-obtained mixture was extracted with THF(three times). The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The residue was separated bychromatography on a silica gel column (eluent: ethylacetate/hexane=1/1→2/1), whereby 2.27 g of Compound 6 and 62 mg ofCompound 7 were obtained (yields: 50% and 1%, respectively).

REFERENTIAL EXAMPLE 7

[0148] Synthesis of3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one 1,1-dioxide(Compound 8) and3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepin-5-one 1,1-dioxide(Compound 9)

[0149] A mixture consisting of 6.00 g (27.5 mmol) of Compound 5 and 300g of polyphosphoric acid was stirred for 1 hour over an oil bath of 100°C. The reaction mixture was ice-cooled and was then poured into icewater. A concentrated aqueous solution of sodium hydroxide was added toadjust the pH to 4. Subsequent to saturation with sodium chloride, theresulting mixture was extracted with THF (3 times). The organic layerwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was separated by chromatography on a silica gelcolumn (eluent: ethyl acetate/hexane=2/1), whereby 2.50 g of Compound 8and 497 mg of Compound 9 were obtained (yields: 46% and 9%,respectively).

EXAMPLE 1

[0150] Synthesis of Sodium 1-methylpyrrole-3-sulfonate Monohydrate(Compound 10)

[0151] Under an argon gas atmosphere, a solution of 9.44 g (50 mmol) oftrimethylsilyl chlorosulfonate in 50 ml of carbon tetrachloride wasgradually added under stirring to a solution of 18.5 g (50 mmol) of1-methyl-2-tri-n-butylstannylpyrrole in 150 ml of carbon tetrachloride,followed by stirring at 50° C. for 30 minutes and further at roomtemperature for 30 minutes. To the reaction mixture, 300 ml of asaturated aqueous solution of sodium hydrogencarbonate were added,followed by stirring at room temperature for 20 minutes. The reactionmixture was allowed to separate into two layers. The water layer wascollected and then washed with ethyl ether (100 ml×3 times). From thewater layer, water was distilled off under reduced pressure, followed bythe addition of ethanol to the residue. The resulting mixture was boiledand then subjected to hot filtration. The solvent in the filtrate wasdistilled off under reduced pressure, and the thus-obtained solid waswashed with n-pentane (200 ml×2 times) and then dried under reducedpressure. Colorless powdery crystals (6.67 g) were obtained.

EXAMPLE 2

[0152] Synthesis of sodium 1-methylpyrrole-3-sulfonate monohydrate(Compound 10) (Alternative Process)

[0153] A mixture consisting of 48.3 g (595 mmol) of 1-methylpyrrole, 100g (628 mmol) of sulfur trioxide-pyridine complex and 325 ml of1,2-dichloroethane was refluxed for 24 hours. The top layer of thereaction mixture was removed by decantation, and 225 ml of water and 100g of sodium carbonate were successively added to the residue. Theresulting mixture was boiled, and the solvent was distilled off underreduced pressure. Ethanol-water (9:1 v/v, 1167 ml) was added to theresidue. The thus-obtained mixture was refluxed for 30 minutes and wasthen subjected to hot filtration. The filtrate was concentrated underreduced pressure and the residue was recrystallized from water-ethanol,whereby 7.05 g of powdery crystals were obtained.

EXAMPLE 3

[0154] Synthesis of benzyl 2-[3-(1-methylpyrrole)sulfonamide]propionate(Compound 11)

[0155] A suspension of 7.40 g (36.8 mmol) of the sodium1-methylpyrrole-3-sulfonate monohydrate obtained in Example 1 and 9.25 g(44.4 mmol) of phosphorus pentoxide in 303 ml of diethyl ether wasstirred at room temperature for 2 hours. The reaction mixture wasfiltered, and the filtrate was washed successively with chilled water, achilled, half-saturated aqueous solution of sodium hydrogencarbonate,chilled water and a chilled, saturated aqueous solution of sodiumchloride. The organic layer was dried over anhydrous sodium sulfate andthen concentrated under reduced pressure, whereby 4.14 g of3-(1-methylpyrrole)sulfonyl chloride were obtained as crude crystals.

[0156] After a mixture consisting of the whole amount of thethus-obtained crude crystals, 12.18 g (34.65 mmol) of β-alanine benzylester p-toluenesulfonate, 7.01 g (69.3 mmol) of triethylamine and 200 mlof THF was refluxed for 17 hours, the reaction mixture was allowed tocool down and was then filtered. The filtrate was concentrated underreduced pressure. Ethyl acetate was added to the residue. The resultingmixture was washed successively with water, a 10% aqueous solution ofcitric acid, water and a saturatred aqueous solution of sodium chloride,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (eluent: ethyl acetate/hexane=1/1), whereby 5.97 g of the titlecompound were obtained (yield: 50%).

EXAMPLE 4

[0157] Synthesis of 3-[3-(1-methylpyrrole)sulfonamide]-propionic Acid(Compound 12)

[0158] To a solution of 5.595 g (17.36 mmol) of Compound 11 in 200 ml ofTHF, 560 mg of 5% palladium on charcoal were added, followed by stirringat room temperature for 24 hours under a hydrogen gas stream. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was recrystallized from2-propanol-diisopropyl ether, whereby 3.49 g of the title compound wereobtained (yield: 81%).

EXAMPLE 5

[0159] Synthesis of5-methyl-2,3,4,5-tetrahydropyrrolo-[2,3-e][1,2]thiazin-4-one 1,1-dioxide(Compound 13)

[0160] A suspension of 2.06 g (14 mmol) of Compound 6, 1.3 ml (14 mmol)of dimethyl sulfate, 1.90 g (14 mmol) of potassium carbonate in 140 mlof acetone was stirred at room temperature for 5 hours. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (eluent: THF/methylene chloride=1/7), whereby 2.40 g of the titlecompound were obtained (yield: 86%).

EXAMPLE 6

[0161] Synthesis of6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one1,1-dioxide (Compound 14)

[0162] A suspension of 200 mg (1 mmol) of Compound 8, 126 mg (1 mmol) ofdimethyl sulfate and 138 mg (1 mmol) of potassium carbonate in 20 ml ofacetone was refluxed for 12 hours. The reaction mixture was concentratedunder reduced pressure, followed by the addition of a saturated aqueoussolution of sodium chloride to the residue. The resultant mixture wasextracted with chloroform (3 times). The organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The residue was purified by chromatography on a silica gel column,(eluent: methanol/chloroform=1/19), whereby 135 mg of the title compoundwere obtained (yield: 63%).

EXAMPLE 7

[0163] Synthesis of7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepin-5-one1,1-dioxide (Compound 15)

[0164] A suspension of 480 mg (2.4 mmol) of Compound 9, 303 mg (2.4mmol) of dimethyl sulfate and 332 mg (2.4 mmol) of potassium carbonatein 50 ml of acetone was stirred at room temperature for 22 hours. Thereaction mixture was concentrated under reduced pressure, and water and1 g of citric acid were added to the residue. The thus-obtained mixturewas extracted with chloroform (3 times). The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The residue was purified by chromatography on a silica gel column(eluent: methanol/chloroform=1/19), whereby 347 mg of the title compoundwere obtained (yield: 68%).

EXAMPLE 8

[0165] Synthesis of7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepin-5-one1,1-dioxide (Compound 15) (Alternative Process)

[0166] A mixture consisting of 497 mg (2 mmol) of Compound 12 and 25 gof polyphosphoric acid was stirred for 1 hour over an oil bath of 100°C. The reaction mixture was added to about 200 ml of ice water, andpotassium carbonate was added to adjust the pH to 4. Subsequent tosaturation with sodium chloride, the resultant mixture was extractedwith chloroform (3 times). The organic layer was washed with water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:ethyl acetate), whereby 80 mg of the title compound were obtained(yield: 17%).

EXAMPLE 9

[0167] Synthesis of2-(3-chloropropyl)-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazin-4-one1,1-dioxide (Compound 16)

[0168] A suspension of 200 mg (1 mmol) of Compound 13, 189 mg (1.2 mmol)of 1-bromo-3-chloropropane and 345 mg (2.5 mmol) of potassium carbonatein 5 ml of acetone was refluxed for 6 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:ethyl acetate/methylene chloride=1/30), whereby 125 mg of the titlecompound were obtained (yield: 45%).

EXAMPLE 10

[0169] Synthesis of2-(3-bromopropyl)-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazin-4-one1,1-dioxide (Compound 17)

[0170] A suspension of 500 mg (2.5 mmol) of Compound 13, 2.5 g (12.5mmol) of 1,3-dibromopropane and 690 mg (5 mmol) of potassium carbonatein 25 ml of acetone was refluxed for 12 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:ethyl acetate/methylene chloride=1/40), whereby 274 mg of the titlecompound were obtained (yield: 34%).

EXAMPLE 11

[0171] Synthesis of2-(3-chloropropyl)-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one1,1-dioxide (Compound 18)

[0172] A suspension of 214 mg (1 mmol) of Compound 14, 630-mg (4-mmol)of 1-bromo-3-chloropropane and 276 mg (2 mmol) of potassium carbonate in5 ml of acetone was refluxed for 6 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:ethyl acetate/hexane=1/2), whereby 275 mg of the title compound wereobtained (yield: 95%).

EXAMPLE 12

[0173] Synthesis of2-(3-chloropropyl)-4-hydroxyimino-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazine1,1-dioxide (Compound 19)

[0174] A suspension of 300 mg (1.08 mmol) of Compound 16, 113 mg (1.62mmol) of hydroxylamine hydrochloride and 159 mg (1.62 mmol) of potassiumacetate in 10 ml of methanol was refluxed for 7 hours. To the reactionmixture, 75 mg (1.08 mmol) of hydroxylamine hydrochloride and 106 mg(1.08 mmol) of potassium acetate were added, followed by furtherrefluxing for 13 hours. Post treatment and purification were conductedas in Example 9, whereby 277 mg of the title compound were obtained(yield: 88%).

EXAMPLE 13

[0175] Synthesis of2-(3-chloropropyl)-5-hydroxyimino-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]-thiazepine-1,1-dioxide(Compound 20)

[0176] A suspension of 404 mg (1.39 mmol) of Compound 18, 290 mg (4.17mmol) of hydroxylamine hydrochloride and 342 mg (4.17 mmol) of sodiumacetate in 40 ml of methanol was refluxed for 22 hours. To the reactionmixture, 97 mg (1.39 mmol) of hydroxylamine hydrochloride and 114 mg(1.39 mmol) of sodium acetate were added, followed by further refluxingfor 19 hours. The reaction mixture was concentrated under reducedpressure and a half-saturated aqueous solution of potassium carbonatewas added to the residue. The thus-obtained mixture was extracted withchloroform (3 times). The organic layer was washed successively withwater and a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The residue was purified by chromatography on a silica gel column(eluent: chloroform), whereby 338 mg of the title compound were obtained(yield: 80%).

EXAMPLE 14

[0177] Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-methyl-2,3,4,5-tetrahydropyrrolo-[2,3-e][1,2]thiazin-4-one1,1-dioxide (Compound 21)

[0178] A suspension of 54 mg (0.17 mmol) of Compound 17, 46 mg(0.25-mmol) of 1-(4-fluorophenyl)piperazine and 57 mg (0.68 mmol) ofsodium hydrogencarbonate in 3.4 ml of dioxane was refluxed for 7 hours.Post treatment and purification were conducted as in Example 9, whereby67 mg of the title compound were obtained (yield: 94%).

EXAMPLE 15

[0179] Synthesis of2-[3-[4-(4-fluorobenzoyl)piperidino]propyl]-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one1,1-dioxide (Compound 22)

[0180] A suspension of 116 mg (0.4 mmol) of Compound 18, 97 mg (0.4mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6 mmol)of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 5ml of acetonitrile was refluxed for 17 hours. Post treatment wasconducted as in Example 13, and the residue was purified bychromatography on a silica gel column (eluent:methanol/chloroform=3/97), whereby 137 mg of the title compound wereobtained (yield: 74%).

EXAMPLE 16

[0181] Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one1,1-dioxide (Compound 23)

[0182] A suspension of 116 mg (0.4 mmol) of Compound 18, 108 mg (0.6mmol) of 1-(4-fluorophenyl)piperazine, 83 mg (0.6 mmol) of potassiumcarbonate and 120 mg (0.8 mmol) of sodium iodide in 6 ml of acetonitrilewas refluxed for 19 hours. The reaction mixture was concentrated underreduced pressure, a half-saturated aqueous solution of potassiumcarbonate was added to the residue, and the resultant mixture wasextracted with ethyl acetate. The organic layer was washed successivelywith water and a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (eluent: methanol/chloroform=3/97), whereby 173 mg of the titlecompound were obtained (yield: 100%).

EXAMPLE 17

[0183] Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepin-5-one1,1-dioxide (Compound 24)

[0184] A suspension of 236 mg (1.1 mmol) of Compound 15, 308 mg (1.2mmol) of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine and 304 mg (2.2mmol) of potassium carbonate in 15 ml of 2-butanone was refluxed for 16hours. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (eluent: ethyl acetate), whereby276 mg of the title compound were obtained (yield: 58%).

EXAMPLE 18

[0185] Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hydroxyimino-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazine1,1-dioxide (Compound 25)

[0186] A suspension of 116 mg (0.4 mmol) of Compound 19, 108 mg (0.6mmol) of 1-(4-fluorophenyl)piperazine, 134 mg (1.6 mmol) of sodiumhydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 8 ml ofacetonitrile was refluxed for 23 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:methanol/methylene chloride=1/20), whereby-152 mg of the title compoundwere obtained (yield: 87%).

EXAMPLE 19

[0187] Synthesis of2-[3-[4-(4-fluorobenzoyl)piperidino]-propyl]-4-hydroxyimino-5-methyl-2,3,4,5-tetrahydropyrrolo-[2,3-e][1,2]thiazine1,1-dioxide (Compound 26)

[0188] A suspension of 116 mg (0.4 mmol) of Compound 19, 389 mg (0.6mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6 mmol)of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 8ml of acetonitrile was refluxed for 24 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:methanol/methylene chloride=1/15), whereby 90 mg of the title compoundwere obtained (yield: 49%).

EXAMPLE 20

[0189] Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-hydroxyimino-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepine1,1-dioxide (Compound 27)

[0190] A suspension of 112 mg (0.4 mmol) of Compound 20, 108 mg (0.6mmol) of 1-(4-fluorophenyl)piperazine, 83 mg (0.6 mmol) of potassiumcarbonate and 120 mg (0.8 mmol) of sodium iodide in 6 ml of acetonitrilewas refluxed for 18 hours. The reaction mixture was concentrated underreduced pressure, and a half-saturated aqueous solution of potassiumcarbonate was added to the residue. The water layer was saturated withsodium chloride, and the thus-obtained mixture was extracted with THF.The organic layer was dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (eluent:methanol/chloroform=3/97), whereby 53 mg of the title compound wereobtained (yield: 29%).

EXAMPLE 21

[0191] Synthesis of2-[3-[4-(4-fluorobenzoyl)piperidino]-propyl]-5-hydroxyimino-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepine1,1-dioxide (Compound 28)

[0192] A suspension of 112 mg (0.4 mmol) of Compound 20, 97 mg (0.4mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6 mmol)of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 5ml of acetonitrile was refluxed for 14 hours. Post treatment andpurification were conducted as in Example 15, whereby 181 mg of thetitle compound were obtained (yield: 95%).

EXAMPLE 22

[0193] Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hydroxy-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazine1,1-dioxide (Compound 29)

[0194] To a suspension of 42 mg (0.1 mmol) of Compound 21 in 5 ml ofethanol, 38 mg (1 mmol) of sodium borohydride were added gradually underice-cooled stirring. The resulting mixture was stirred under ice coolingfor 1 hour and further at room temperature for 13 hours. Water (5 ml)was added to the reaction mixture. The thus-obtained mixture was stirredat room temperature for 5 hours and then concentrated under reducedpressure. Post treatment and purification were conducted as in Example15, whereby 36 mg of the title compound were obtained (yield: 85%).

EXAMPLE 23

[0195] Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-hydroxy-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepine1,1-dioxide (Compound 30)

[0196] To a suspension of 240 mg (0.57 mmol) of Compound 23 in 5 ml ofethanol, 200 mg (5.3 mmol) of sodium borohydride were added graduallyunder ice-cooled stirring. The resulting mixture was stirred under icecooling for 1 hour and further at room temperature for 4 hours. Asaturated aqueous solution of ammonium chloride was added to thereaction mixture under ice cooling, followed by the addition of asaturated aqueous solution of sodium hydrogencarbonate so that themixture was alkalinized. The water layer was extracted with methylenechloride. The organic layer was dried over anhydrous magnesium sulfateand then concentrated under reduced pressure. The residue was purifiedby chromatography on a silica gel column (eluent: methanol/methylenechloride=1/20), whereby 186 mg of the title compound were obtained(yield: 77%).

EXAMPLE 24

[0197] Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-hydroxy-7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepine1,1-dioxide (Compound 31)

[0198] To a suspension of 174 mg (0.4 mmol) of Compound 24 in 8 ml ofethanol, 151 mg (4 mmol) of sodium borohydride were added graduallyunder ice-cooled stirring. The resulting mixture was stirred under icecooling for 1 hour and further at room temperature for 13 hours. Water(80 ml) was added to the reaction mixture. The thus-obtained mixture wasstirred at room temperature for 30 minutes and then concentrated underreduced pressure. Post treatment and purification were conducted as inExample 15, whereby 151 mg of the title compound were obtained (yield:86%).

[0199] Physical data of the compounds obtained in Examples 1-24 areshown in Tables 1-6. TABLE 1 Comp'd Structural Property NMR (δ ppm)* IR(cm⁻¹) No. formula m.p. (recryst'n solvent) ( ): observation frequency (): measuring method 10

Colorless powdery crystals ≧250° C. (400 MHz) (D₂O/TSP-d₄**) 3.67 (3H,s), 6.37 (1H, s), 6.75 (1H, s), 7.11 (1H, s) (KBr) 3446, 3132, 1636,1526, 1186, 1148, 1060, 1048, 942, 802, 699, 662 11

Colorless oil (400 MHz) 2.60 (2H, t, J=6.2Hz), 3.23 (2H, m), 3.66 (3H,s), 4.93 (1H, br. t), 6.38 (1H, m), 6.59 (1H,m), 7.11 (1H, m), 7.28-7.41(5H, m) (film) 3283, 1732, 1519, 1323, 1155, 1119, 801, 699 12

Pale yellow powdery crystals 95.5-98.0° C. (isopropanol- Isopropylether) (400 MHz) (DMSO-d₄/TMS) 2.37 (2H, t, J=7.2Hz), 2.92 (2H, m), 3.66(3H, s), 6.27 (1H, m), 6.83 (1H, m), 6.99 (1H, br), 7.25 (1H, m), 12.18(1H, br) (KBr) 3281, 1718, 1522, 1422, 1310,1241, 1150, 1040, 801, 688

[0200] TABLE 2 Comp'd Structural Property NMR (δ ppm)* IR (cm⁻¹) No.formula m.p. (recryst'n solvent) ( ): observation frequency ( ):measuring method 13

Colorless powdery crystals 142.0-143.0° C. (ethyl acetate-hexane) (270MHz)3.98 (3H, s), 4.16 (2H, d, J=7.3Hz), 5.30 (1H, t, J=7.3Hz), 6.55(1H, d, J=2.6Hz), 6.91 (1H, d, J=2.6Hz) (KBr) 3196, 1673, 1648, 1382,1328, 1307, 1209, 1162, 1142, 1083, 762 14

Colorless prism crystals 132.0-133.5° C. (chloroform) (270 MHz)(DMSO-d₄/TMS) 3.01 (2H, m), 3.33 (2H, m), 3.82 (3H, s), 6.52 (1H, d,J=2.6Hz), 7.22 (1H, d, J=2.6Hz), 7.86 (1H, t, J=5.6Hz) (KBr) 3303, 1652,1481, 1403, 1321, 1200, 1151, 1094, 1018, 983, 866, 783, 766, 674 15

Pale yellow prism crystals 135.0-138.0° C. (ethyl) acetate- isopropylether) (400 MHz) (DMSO-d₄/TMS) 2.83 (2H, m), 3.38 (2H, m), 3.68 (3H, s),7.43 (1H, d, J=2.4Hz), 7.45(1H, d, J=2.4Hz), 7.75 (1H, br. s.) (KBr)3235, 1642, 1538, 1322, 1242, 1153, 1050, 858, 755 16

Colorless prism crystals 96.0-97.0° C. (ethyl acetate-hexane) (270 MHz)2.08 (2H, quint., J=6.6Hz), 3.35 (2H, t, J=6.6 Hz), 3.65 (2H, t,J=6.6Hz), 3.99 (3H, s), 4.22 (2H, s), 6.53 (1H, d, J=2.6Hz), 6.92 (1H,d, J=2.6Hz) (KBr) 1680, 1387, 1326, 1210, 1150, 1011, 900, 774, 705

[0201] TABLE 3 Comp'd Structural Property NMR (δ ppm)* IR (cm⁻¹) No.formula m.p. (recryst'n solvent) ( ): observation frequency ( ):measuring method 17

Colorless prism crystals 84.0-85.0° C. (ethyl acetate-hexane) (270 MHz)2.16 (2H, quint., J=6.6Hz), 3.34 (2H, t, J=6.6Hz), 3.50 (2H, t,J=6.6Hz), 3.99 (3H, s), 4.23 (2H, s), 6.53 (1H, d, J=2.6Hz), 6.91 (1H,d, J=2.6Hz) (KBr) 1680, 1484, 1389, 1328, 1260, 1212, 1149, 1006, 898,715 18

Colorless needle crystals 71.0-74.0° C. (ethyl acetate-hexane) (270 MHz)2.04 (2H, quint., J=6.6Hz), 3.17 (2H, t, J=6.6Hz), 3.25 (2H, m),3.53-3.67 (4H, m), 3.92 (3H, s), 6.66 (1H, d, J=2.6Hz), 6.81(1H, d,J=2.6Hz) (KBr) 3120, 2964, 1661, 1472, 1405, 1375, 1330, 1213, 1196,1152, 1096, 1026, 964, 854, 757, 707 19

Colorless prism crystals 126.0-127.0° C. (ethyl acetate-hexane) (270MHz) 2.09 (2H, quint., J=6.6Hz), 3.17 (2H, t, J=6.6Hz), 3.67 (2H, t,J=6.6Hz), 3.84 (3H, s), 4.64 (2H, s), 6.48 (1H, d, J=2.6Hz), 6.71 (1H,d, J=2.6Hz), 7.53 (1H, s) (KBr) 3465, 1610, 1483, 1365, 1298, 1207,1148, 1023, 994, 936, 848, 795 20

Colorless prism crystals 110.0-111.0° C. (ethyl acetate-hexane) (400 MHz2.04 (2H, quint., J=6.4Hz), 3.15-3.21 (4H, m), 3.60-3.66 (4H, m), 3.73(3H, s), 6.57 (1H, d, J=2.9Hz), 6.60 (1H, d, J=2.9Hz), 7.59 (1H, s)(KBr) 3358, 3120, 2949, 1486, 1413, 1308, 1194, 1142, 1062, 988, 953,936, 907, 870, 757, 730, 707

[0202] TABLE 4 Property Comp'd Structural m.p. (recryst'n NMR (δ ppm)*IR (cm⁻¹) No. formula solvent) ( ): observation frequency ( ): measuringmethod 21

Colorless needle crystals 141.0-142.0° C. (ethyl acetate- hexane) (270MHz) 1.81 (2H, quint., J=7.3Hz), 2.47 (2H, t, J=7.3Hz), 2.58 (4H, m),3.11 (4H, m), 3.27 (2H, t, J=7.3Hz), 3.98 (3H, s), 4.23 (2H, s), 6.52(1H, d, J=2.6Hz), 6.84-6.99 (5H, m) (KBr) 2950, 2833, 1684, 1510, 1386,1335, 1238, 1155, 1005, 900, 815, 782, 7.19 22

Colorless powdery crystals 105.0-107.0° C. (ethyl acetate- hexane) (270MHz) 1.69-1.89 (6H, m), 2.06 (2H, m), 2.41 (2H, m), 2.95 (2H, m), 3.06(2H, t, J=7.3Hz), 3.18 (1H, m), 3.24 (2H, m), 3.56 (2H, m), 3.92 (3H,s), 6.65 (1H, d, J=2.6Hz), 6.80 (1H, d, J=2.6Hz), 7.14 (2H, m), 7.96(2H, m) (KBr) 2948, 2778, 1726, 1668, 1596, 1508, 1464, 1405, 1375,1322, 1228, 1146, 1046, 980, 856, 755 23

Colorless powdery crystals 72.0-73.5° C. (ethyl acetate- hexane) (270MHz) 1.77 (2H, quint., J=7.3Hz), 2.44 (2H, t, J=7.3Hz), 2.57 (4H, m),3.03-3.14 (6H, m), 3.25 (2H, m), 3.56 (2H, m), 3.92 (3H, s), 6.65 (1H,d, J=2.6Hz), 6.80 (1H, d, J=2.6Hz), 6.87 (2H, m), 6.95 (2H, m) (KBr)3609, 3128, 2842, 1661, 1508, 1452, 1404, 1386, 1318, 1247, 1216, 1143,1038, 1014, 980, 958, # 930, 846, 828, 780, 710 24

Colorless of 1 (400 MHz) 1.81 (2H, quint., J=7.0Hz), 2.46 (2H, t,J=7.0Hz), 2.58 (4H, m), 3.05 (2H, m), 3.10 (4H, m), 3.16 (2H, t,J=7.0Hz), 3.68 (2H, m), 3.71 (3H, s), 6.86 (2H, m), 6.95 (2H, m), 7.14(1H, d, J=2.5Hz), 7.25 (1H, d, J=2.5Hz) (film) 3124, 2945, 2819, 1655,1531, 1509, 1456, 1329, 1232, 1156, 1038, 959, 827, 717

[0203] TABLE 5 Property Comp'd Structural m.p. (recryst'n NMR (δ ppm)*IR (cm⁻¹) No. fomula solvent) ( ): observation frequency ( ): measuringmethod 25

Colorless needle crystals 177.0-178.0° C. ethanol) (270 MHz)(DMSO-d₄/TMS) 1.71 (2H, m), 2.38 (2H, t, J=6.6Hz), 2.47 (4H, m), 2.94(2H, t, J=6.6Hz), 3.05 (4H, m), 3.83 (3H, s), 4.51 (2H, s), 6.42 (1H, d,J=3.3Hz), 6.93 (2H, m), 7.02 (2H, m), 7.06 (1H, d, J=3.3Hz), 11.89 (1H,s) (KBr) 2833, 1513, 1332, 1244, 1203, 1156, 950, 824, 725, 695 26

Colorless needle crystals 209.0-210.0° C. (decomp'd) (ethanol) (270 MHz)(DMSO-d₄/TMS) 1.56 (2H, m), 2.64-2.78 (4H, m), 2.04 (2H, m), 2.33 (2H,m), 2.85-2.95 (4H, m), 3.35 (1H, m), 3.84 (3H, s), 4.49 (2H, s), 6.42(1H, d, J=3.3Hz), 7.08 (1H, d, J=3.3Hz), 7.34 (2H, m), 8.04 (2H, m),11.89 (1H, s) (KBr) 2953, 1684, 1598, 1508, 1412, 1330, 1206, 1157, 973,942, 837, 778, 739, 721 27

Colorless powdery crystals 237.0-239.0° C. (acetonitrile- isopropylether) (400MHz) (DMSO-d₄/TMS) 1.69 (2H, quint., J=6.9Hz), 2.33 (2H, m),2.48 (4H, m), 2.93 (2H, m), 2.99 (2H, t, J=6.9Hz), 3.05 (4H, m), 3.55(2H, m), 3.67 (3H, s), 6.37 (1H, d, J=2.9Hz), 6.89 (1H, d, J=2.9Hz),6.92 (2H, m), 7.02 (2H, m), 11.78 (1H, s) (KBr) 2960, 2824, 1509, 1448,1323, 1245 1231, 1195, 1150 1040, 993, # 995, 924, 816, 757, 728, 706 28

Colorless powdery crystals 192.5-195.0° C. (ethyl acetate- hexane) (400MHz) 1.72-1.96 (6H, m), 2.14 (2H, m), 2.46 (2H, M), 2.99-3.08 (4H, m),3.16-3.28 (3H, m), 3.55 (2H, m), 3.75 (3H, s), 6.56 (1H, d, J=3.0Hz),6.59 (1H, d, J=3.0Hz), 7.14 (2H, m), 7.95 (2H, m), 10.13 (1H, br. s)(KBr) 3402, 2953, 1680, 1597, 1505, 1450, 1412, 1327, 1196, 1150, 993,973, 855, 726, 700

[0204] TABLE 6 Property Comp'd Structural m.p. (recryst'n NMR (δ ppm)*IR (cm⁻¹) No. formula solvent) ( ): observation frequency ( ): measuringmethod 29

Colorless powdery crystals 157.5-161.50° C. (ethyl acetate- hexane) (400MHz) 1.83 (2H, m), 2.35 (2H, m), 2.46 (1H, m), 2.61 (2H, m), 2.70 (1H,m), 2.82 (2H, m), 2.95-3.05 (3H, m), 3.52 (1H, dd, J=2.0Hz, 14.8Hz),3.63 (3H, s), 3.92 (1H, m), 4.20 (1H, dd, J=2.8Hz, 14.8Hz), 4.52 (1H, t,J=2.3Hz), 6.44 (1H, d, J=3.0Hz), 6.60 (1H, d, J=3.0Hz), 6.79 (2H, m)6.94 (2H, m) (KBr 3528, # 2953, 2820 2360, 1510, 1464, 1310, 1232, 1209,1140, 1059, 1003, 958, 920, 815, 776, 738, 713 30

Colorless oil (270 MHz) 1.82 (2H, quint.,J=7.3Hz), 1.93 (1H, m), 2.14(1H, m), 2.40 (1H, m), 2.49-2.65 (5H, m), 2.78 (1H, m), 3.10 (4H, m),2.25-2.38 (2H, m), 3.67 (3H, s), 4.40 (1H, m), 4.92 (1H, m), 6.43-6.45(2H, m), 6.87 (2H, m), 6.95(2H, m) (film) 3500, 2822, 1731, 1505, 1455,1232, 1138, 930, 818, 706 31

Colorless plate crystals 165.5-169.0° C. (ethyl acetate- hexane) (400MHz) 1.81 (2H quint., J=7.1Hz), 1.92 (2H, m), 2.47 (2H, m), 2.59 (4H,m), 2.83 (1H, m), 3.05-4.05 (6H, m), 3.44 (1H, m), 3.62 (3H, s), 4.12(1H, m), 4.87 (1H, br. s), 6.56 (1H, d, J=2.4Hz), 6.87 (2H, m), 6.95(2H, m), 7.02 (1H, d, J=2.4Hz) (KBr) 3122, 2959, 2828, 1509, 1448, 1328,1247, 1151, 1124, 1062, # 1009, 928, 897, 830, 780, 758, 711, 692

[0205] Tests

[0206] With respect to certain compounds of the present invention, theiranti-serotonin (5-HT) action and anti-α₁ action were investigated by themethods which will be described below. The results of somerepresentative compounds are shown in Table 7.

[0207] (1) Anti-Serotonin (5-HT) Action

[0208] The superior mesenteric artery of each Hartley male guinea pig(body weight: 300-500 g) was excised. A preparation cut in a helicalform was suspended under resting-tension of 0.3 g in a Magnus cylinderfilled with the Tyrode solution which had been aerated with a gasmixture of 95% O₂ and 5% CO₂ and maintained at 37° C. Using an isometrictransducer (“UL-10”, manufactured by SHINKOH K.K.) and a pressurepreamplifier (“DSA-605A”, manufactured by SHINKOH K.K.), variations intension were measured. The isometric tensions were recorded on apen-writing recorder (“VP-6537A”, manufactured by NATIONAL K.K.). Takingthe contraction induced by 10⁻⁵ M serotonin (5-HT) as 100%, the percentcontractions by 10⁻⁵ M 5-HT in the presence of each test drug at 10⁻⁷ Mand 10⁻⁶ M were determined as anti-5-HT action.

[0209] (2) Anti-α₁ Action

[0210] The thoracic aorta of each Hartley male guinea pig (body weight:300-500 g) was excised. A preparation cut in a helical form wassuspended under 1 g load in a Magnus cylinder filled with the Tyrodesolution which had been aerated with a gas mixture of 95% O₂ and 5% CO₂and maintained at 37° C. Using an isometric transducer (“TB-612J”,manufactured by Nihon Kohden Corporation) and a pressure preamplifier(“AP-620G”, manufactured by Nihon Kohden Corporation), variations intension were measured. The isometric tensions were recorded on a thermalpen-writing recorder (“WT-647G”, manufactured by Nihon KohdenCorporation). Taking the tonic contraction induced by 10⁻⁵ Mnorepinephrine (NE) as 100%, the percent contractions upon addition ofeach test drug at 10⁻⁸ M and 10⁻⁷ M were determined and recorded as α₁action. TABLE 7 Anti 5-HT action Anti α₁ action Comp'd (% of Control) (%of Control) No. 10⁻⁷M 10⁻⁶M 10⁻⁸M 10⁻⁷M 22 75.3 21.3 91.2 64.9 25 69.819.6 65.3 24.1 26 54.6 18.2 99.6 73.1 27 76.2 22.7 91.2 53.0 30 83.537.2 102.3  88.0

[0211] Capability of Exploitation in Industry

[0212] The pyrrolesulfonamide derivatives (I) and their salts accordingto the present invention have strong serotonin-2 blocking action andhave high safety. Accordingly, the present invention has made itpossible to provide pharmaceuticals making use of antagonistic actionagainst serotonin-2 receptors, for example, therapeutics for variouscirculatory diseases such as ischemic heart diseases, cerebrovasculardisturbances and peripheral circulatory disturbances. Further, thecompounds according to the present invention include those also havinga, blocking action in combination. Since these compounds are alsoeffective as antihypertensives, they are extremely used for therapeuticsfor a wide variety of circulatory diseases.

1. A pyrrolesulfonamide derivative or a salt thereof, saidpyrrolesulfonamide derivative being represented by the following formula(I):

wherein the ring p represented by

means a pyrrole ring represented by the following structure:

in which R represents an alkyl group, a cycloalkyl group, acycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;the dashed line indicates the presence or absence of a bond; and, whenthe bond indicated by the dashed line is present, Z₂ is not present andZ₁ represents a hydrogen atom but, when the bond indicated by the dashedline is absent, Z₁ represents a hydrogen atom and Z₂ represents ahydroxyl group; or Z₁ and Z₂ are combined together to represent anoxygen atom or a group NOR₁ in which R₁ represents a hydrogen atom, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaralkyl group or a substituted or unsubstituted aryl group; l represents0 or 1; A represents a substituted or unsubstituted alkylene group, asubstituted or unsubstituted alkenylene group or a substituted orunsubstituted alkynylene group; and Y represents a group

in which W represents CH, C═ or a nitrogen atom; and, when W representsCH, m stands for 0 or 1, B represents a carbonyl group, a sulfonylgroup, an alkylene group, an alkenylene group, a group —C(OH)R₂— inwhich R₂ represents a substituted or unsubstituted aryl group, a group—CHR₃— in which R₁ represents a substituted or unsubstituted aryl group,or a substituted or unsubstituted cyclic or acyclic acetal group; when Wrepresents C═, m stands for 1, B represents a group

in which the double bond is coupled with W and R₄ represents asubstituted or unsubstituted aryl group-or a substituted orunsubstituted aralkyl group; when W represents a nitrogen atom, m standsfor 0 or 1, and B represents a carbonyl group, a sulfonyl group, analkylene group, an alkenylene group or a group —CHR₅— in which R₅represents a substituted or unsubstituted aryl group; E₁ and E₂ eachindependently represents a hydrogen atom or a lower alkyl group; and Drepresents a substituted or unsubstituted aromatic hydrocarbon group ora substituted or unsubstituted aromatic heterocyclic group.
 2. Apyrrolesulfonamide derivative or a salt thereof according to claim 1,wherein in the formula (I), Z₁ represents a hydrogen atom and Z₂represents a hydroxyl group.
 3. A pyrrolesulfonamide derivative or asalt thereof according to claim 1, wherein in the formula (I), Z₁ and Z₂are combined together to represent an oxygen atom or a group NOH.
 4. Apyrrolesulfonamide derivative or a salt thereof according to claim 1, 2or 3, wherein in the formula (I), A is a trimethylene group.
 5. Apyrrolesulfonamide derivative or a salt thereof according to claim 1, 2,3 or 4, wherein in the formula (I), W represents a nitrogen atom, mstands for 0, and D represents a substituted or unsubstituted phenylgroup.
 6. A pyrrolesulfonamide derivative or a salt thereof according toclaim 1, 2, 3, 4 or 5, wherein in the formula (I), E₁ and E₂ bothrepresent hydrogen atoms.
 7. A pyrrolesulfonamide derivative or a saltthereof according to claim 1, 2, 3, 4, 5 or 6, wherein in the formula(I), the ring P represents the following formula:

wherein R has the same meaning as defined above.
 8. A process for thepreparation of a pyrrolesulfonamide derivative represented by thefollowing formula (Ia):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: reacting a compound, which is represented by thefollowing formula (III): X-A-X′  (III) wherein A has the same-meaning asdefined above and X and X′ represent the same or different eliminativegroups, to a compound represented by the following formula (II):

wherein the ring P and l have the same meanings as defined above,thereby obtaining a compound represented by the following formula (IV):

wherein A, the ring P, X and l have the same meanings as defined above;and then reacting a nitrogen-containing compound represented by thefollowing formula (V): H—Y  (V) wherein Y has the same meaning asdefined above.
 9. A process for the preparation of a pyrrolesulfonamidederivative represented by the following formula (Ia):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: reacting a compound, which is represented by thefollowing formula (VI): X-A-Y  (VI) wherein A, X and Y have the samemeanings as defined above, to a compound represented by the followingformula (II):

wherein the ring P and l have the same meanings as defined above.
 10. Aprocess for the preparation of a pyrrolesulfonamide derivativerepresented by the following formula (Ic):

wherein A, the ring P, R₁ and l have the same meanings as defined above,and Y′ represents a group

in which when W represents CH, B′ represents a sulfonyl group, analkylene group, an alkenylene group, a group —C(OH)R₂— in which R₂represents a substituted or unsubstituted aryl group, a group —CHR₃— inwhich R₃ represents a substituted or unsubstituted aryl group, or asubstituted or unsubstituted cyclic or acyclic acetal group; when Wrepresents C═, B′ represents a group

in which the double bond is coupled with W and R₄ represents asubstituted or unsubstituted aryl group or a substituted orunsubstituted aralkyl group; when W represents a nitrogen atom, B′represents a carbonyl group, a sulfonyl group, an alkylene group, analkenylene group or a group —CHR₅— in which R₅ represents a substitutedor unsubstituted aryl group; and D, E₁, E₂ and m have the same meaningsas defined above, which comprises: reacting a hydroxylamine or aderivative thereof, which is represented by the following formula (VII):NH₂OR₁  (VII) wherein R₁ has the same meaning as defined above, with apyrrolesulfonamide derivative represented by the following formula (Ib):

wherein A, the ring P, Y′ and l have the same meanings as defined above.11. A process for the preparation of a pyrrolesulfonamide derivativerepresented by the following formula (Id):

wherein A, the ring P, Y′ and l have the same meanings as defined above,which comprises: reducing a pyrrolesulfonamide derivative represented bythe following formula (Ib):

wherein A, the ring P, Y′ and l have the same meanings as defined above.12. A process for the preparation of a pyrrolesulfonamide derivativerepresented by the following formula (Ie):

wherein A, the ring P, R₁, Y and l have the same meanings as definedabove, which comprises: reacting a hydroxylamine or a derivativethereof, which is represented by the following formula (VII):NH₂OR₁  (VII) wherein R₁ has the same meaning as defined above, to acompound represented by the following formula (IV):

wherein A, the ring P, X and l have the same meanings as defined above,thereby obtaining a compound represented by the following formula(VIII):

wherein A, the ring P, R₁, X and l have the same meanings as definedabove; and then reacting a nitrogen-containing compound represented bythe following formula (V): H—Y  (V) wherein Y has the same meaning asdefined above.
 13. A process for the preparation of a pyrrolesulfonamidederivative represented by the following formula (If):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: reducing a compound represented by the followingformula (IV):

wherein A, the ring P, X and l have the same meanings as defined above,thereby obtaining a compound represented by the following formula (IX):

wherein A, the ring P, X and l have the same meanings as defined above;and then reacting a nitrogen-containing compound represented by thefollowing formula (V): H—Y  (V) wherein Y has the same meaning asdefined above.
 14. A process for the preparation of a pyrrolesulfonamidederivative represented by the following formula (Ig):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: subjecting a compound, which is represented by thefollowing formula (IX):

wherein A, the ring P, X and l have the same meanings as defined above,to dehydration treatment, thereby obtaining a compound represented bythe following formula (X):

wherein A, the ring P, X and l have the same meanings as defined above;and then reacting a nitrogen-containing compound represented by thefollowing formula (V): H—Y  (V) wherein Y has the same meaning asdefined above.
 15. A process for the preparation of a pyrrolesulfonamidederivative represented by the following formula (Ig):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: subjecting a compound, which is represented by thefollowing formula (If):

wherein A, the ring P, Y and l have the same meanings as defined above,to dehydration treatment.
 16. A compound represented by the followingformula (II):

wherein the ring P and l have the same meanings as defined above.
 17. Acompound represented by the following formula (XI):

wherein the dashed line, A, the ring P, X, Z₁, Z₂ and l have the samemeanings as defined above.
 18. A process for the preparation of apyrrolesulfonamide derivative represented by the following formula (IIa)or (IIa′):

wherein R and l have the same meanings as defined above, whichcomprises: converting a 1-substituted-pyrrole-3-sulfonic acid or a saltthereof, which is represented by the following formula (XII):

wherein M represents a hydrogen ion, an alkali metal ion, an alkalineearth metal ion or a quaternary ammonium ion, p stands for 1 when Mrepresents a hydrogen ion, an alkali metal ion or a quaternary ammoniumion or p stands for 2 when M represents an alkaline earth metal ion, qstands for 0 or 1, and R has the same meaning as defined above, into acompound represented by the following formula (XIII):

wherein X″ represents a chlorine atom or a bromine atom; causing glycineor β-alanine or a derivative thereof, which is represented by thefollowing formula (XIV): NH₂(CH₂)_(l)CH₂COOR₆  (XIV) wherein R₆represents a hydrogen atom or a carboxyl-protecting group, to act,thereby obtaining a compound represented by the following formula (XV):

wherein R, R₆ and l have the same meanings as defined above; and thensubjecting said compound to ring closure.
 19. A process for thepreparation of a pyrrolesulfonamide derivative represented by thefollowing formula (IIa) or (IIa′):

wherein R and l have the same meanings as defined above, whichcomprises: reacting a compound, which is represented by the formula(XVIa) or (XVIb): R—X″′  (XVIa) (RO)₂SO₂  (XVIb) wherein X″′ representsan eliminative group and R has the same meaning as defined above, with acompound represented by the following formula (IIb) or (IIb′):

wherein l has the same meaning as defined above.
 20. A compoundrepresented by the following formula (XV):

wherein R, R₆ and l have the same meanings as defined above.
 21. Acompound represented by the following formula (XII):

wherein M, R, p and q have the same meanings as defined above.
 22. Acompound according to claim 21, wherein in the formula (XII), R is amethyl group, M is a sodium ion, p is 1, and q is 0 or
 1. 23. A processfor the preparation of a 1-substituted-pyrrole-3-sulfonic acid or a saltthere of, which comprises treating a 1-substituted-pyrrole with sulfurtrioxide-pyridine complex.
 24. A process for the preparation of acompound represented by the following formula (XII):

wherein M, R, p and q have the same meanings as defined above, whichcomprises treating a compound, which is represented by the followingformula (XVII):

wherein R has the same meaning as defined above, with trimethylsilylchlorosulfonate, followed by alkali hydrolysis.
 25. A pharmaceuticalcomprising, as an effective ingredient, a pyrrolesulfonamide derivativeor a salt thereof according to claim
 1. 26. A therapeutic forcirculatory diseases, comprising as an effective ingredient apyrrolesulfonamide derivative or a salt thereof according to claim 1.27. A serotonin-2 receptor antagonist, comprising as an effectiveingredient a pyrrolesulfonamide derivative or a salt thereof accordingto claim 1.